PT  - JOURNAL ARTICLE
AU  - Liang Yan
AU  - Bo Tu
AU  - Jun Yao
AU  - Jing Gong
AU  - Alessandro Carugo
AU  - Christopher A. Bristow
AU  - Qiuyun Wang
AU  - Cihui Zhu
AU  - Bingbing Dai
AU  - Ya’an Kang
AU  - Leng Han
AU  - Ningping Feng
AU  - Yanqing Jin
AU  - Jason Fleming
AU  - Timothy P. Heffernan
AU  - Wantong Yao
AU  - Haoqiang Ying
TI  - Targeting glucose metabolism sensitizes pancreatic cancer to MEK inhibition
AID  - 10.1101/2021.01.09.425923
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.01.09.425923
4099  - http://biorxiv.org/content/early/2021/01/11/2021.01.09.425923.short
4100  - http://biorxiv.org/content/early/2021/01/11/2021.01.09.425923.full
AB  - Pancreatic ductal adenocarcinoma (PDAC) is almost universally lethal. A critical unmet need exists to explore essential susceptibilities in PDAC and identify druggable targets for tumor maintenance. This is especially challenging in the context of PDAC, in which activating mutations of KRAS oncogene (KRAS*) dominate the genetic landscape. By using an inducible KrasG12D-driven p53 deficient PDAC mouse model (iKras model), we demonstrate that RAF-MEK-MAPK signaling is the major effector for oncogenic Kras-mediated tumor maintenance. However, MEK inhibition has minimal therapeutic effect as single agent for PDAC both in vitro and in vivo. Although MEK inhibition partially downregulates the transcription of glycolysis genes, it surprisingly fails to suppress the glycolysis flux in PDAC cell, which is a major metabolism effector of oncogenic KRAS. Accordingly, In vivo genetic screen identified multiple glycolysis genes as potential targets that may sensitize tumor cells to MAPK inhibition. Furthermore, inhibition of glucose metabolism with low dose 2-deoxyglucose (2DG) in combination with MEK inhibitor dramatically induces apoptosis in KrasG12D-driven PDAC cell in vitro, inhibits xenograft tumor growth and prolongs the overall survival of genetically engineered mouse PDAC model. Molecular and metabolism analyses indicate that co-targeting glycolysis and MAPK signaling results in apoptosis via induction of lethal ER stress. Together, our work suggests that combinatory inhibition of glycolysis and MAPK pathway may serve as an alternative approach to target KRAS-driven PDAC.Competing Interest StatementThe authors have declared no competing interest.